Over the past three decades, the genes underlying nearly 3,000 Mendelian disorders have been identified by methods such as linkage analysis and positional cloning. Although the availability of a reference human genome greatly accelerated these efforts, there are thousands of additional suspected Mendelian disorders that remain unsolved. An understanding of the genetic basis of a Mendelian disorder can yield fundamental insights into basic human biology and disease pathophysiology, as well as a molecular basis for diagnosis or carrier status determination. In some instances, biological insights from studying Mendelian disorders can prove highly relevant to our understanding of more common diseases. Recently, we and others have shown that the coupling of targeted capture and next-generation DNA sequencing technology can be used to cost-effectively determine nearly all coding variation in an individual human genome, a process termed exome sequencing. We, and others, have also demonstrated how exome sequencing can be applied to efficiently identify the causal genes for Mendelian disorders that have proven intractable to conventional modes of analysis. To accelerate progress towards a comprehensive understanding of the genetic basis of all Mendelian disorders, we propose to establish the UW Center for Mendelian Genomics. Our proposal has four specific aims: (1) To organize samples for all unsolved Mendelian disorders from investigators around the world, either by their submission to our center for sequencing, or by their inclusion on a public sample list that we will develop; (2) To apply our existing production pipeline for exome and genome sequencing to samples corresponding to unsolved Mendelian disorders, and to improve this process through ongoing technology innovation; (3) To determine the genetic basis for as many unsolved Mendelian disorders as possible, through efficient study design and effective, innovative analysis; (4) To take a leadership role in the dissemination of methods and data.